Peroxisome proliferator-activated receptor γ up-regulates the Bcl-2 anti-apoptotic protein in neurons and induces mitochondrial stabilization and protection against oxidative stress and apoptosis

Peroxisome proliferator-activated receptor gamma(PPAR gamma) has been proposed as a therapeutic target for neurodegenerative diseases because of its anti-inflammatory action in glial cells. However, PPAR gamma agonists prevent beta-amyloid (A beta)-induced neurodegeneration in hippocampal neurons, and PPAR gamma is activated by the nerve growth factor (NGF) survival pathway, suggesting a neuroprotective anti-inflammatory independent action. Here we show that the PPAR gamma agonist rosiglitazone (RGZ) protects hippocampal and dorsal root ganglion neurons against A beta-induced mitochondrial damage and NGF deprivation-induced apoptosis, respectively, and promotes PC12 cell survival. In neurons and in PC12 cells RGZ protective effects are associated with increased expression of the Bcl-2 anti-apoptotic protein. NGF-differentiated PC12 neuronal cells constitutively overexpressing PPAR gamma are resistant to A beta-induced apoptosis and morphological changes and show functionally intact mitochondria and no increase in reactive oxygen species when challenged with up to 50 mu M H2O2. Conversely, cells expressing a dominant negative mutant of PPAR gamma show increased A beta-induced apoptosis and disruption of neuronal-like morphology and are highly sensitive to oxidative stress-induced impairment of mitochondrial function. Cells overexpressing PPAR gamma present a 4-to 5-fold increase in Bcl-2 protein content, whereas in dominant negative PPAR gamma-expressing cells, Bcl-2 is barely detected. Bcl-2 knockdown by small interfering RNA in cells overexpressing PPAR gamma results in increased sensitivity to A beta and oxidative stress, further suggesting that Bcl-2 up-regulation mediates PPAR gamma protective effects. PPAR gamma prosurvival action is independent of the signal-regulated MAPK or the Akt prosurvival pathways. Altogether, these data suggest that PPAR gamma supports survival in neurons in part through a mechanism involving increased expression of Bcl-2.